Novel n-3 Fatty Acid Oxidation Products Activate Nrf2 by Destabilizing the Association between Keap1 and Cullin3

• Published in: The Journal of biological chemistry Vol. 282; no. 4; pp. 2529 - 2537
• Main Authors: Gao, Ling, Wang, Jiakun, Sekhar, Konjeti R., Yin, Huiyong, Yared, Nicholas F., Schneider, Scott N., Sasi, Soumya, Dalton, Timothy P., Anderson, Mark E., Chan, Jefferson Y., Morrow, Jason D., Freeman, Michael L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26-01-2007; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cell Cycle Proteins - chemistry; Cell Cycle Proteins - metabolism; Cell Line; Cullin Proteins - chemistry; Cullin Proteins - metabolism; Fatty Acids, Omega-3 - chemistry; Fatty Acids, Omega-3 - metabolism; Gene Expression Regulation; Genes, Reporter; Humans; Intracellular Signaling Peptides and Proteins - chemistry; Intracellular Signaling Peptides and Proteins - metabolism; Kelch-Like ECH-Associated Protein 1; Mice; Molecular Structure; NF-E2-Related Factor 2 - metabolism; Oxidation-Reduction; Oxidative Stress - genetics; Transcriptional Activation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M607622200

Consumption of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can mitigate the progression of diseases in which oxidative stress represents a common underlying biochemical process. Nrf2-regulated gene expression regulates detoxification of reactive oxygen species. EPA and DHA were subjected to an in vitro free radical oxidation process that models in vivo conditions. Oxidized n-3 fatty acids reacted directly with the negative regulator of Nrf2, Keap1, initiating Keap1 dissociation with Cullin3, thereby inducing Nrf2-directed gene expression. Liquid chromatography-tandem mass spectrometry analyses of oxidized EPA demonstrated the presence of novel cyclopentenone-containing molecules termed J3-isoprostanes in vitro and in vivo and were shown to induce Nrf2-directed gene expression. These experiments provide a biochemical basis for the hypothesis that formation of J-ring compounds generated from oxidation of EPA and DHA in vivo can reach concentrations high enough to induce Nrf2-based cellular defense systems.